A 30-year-old woman presents with acute attacks of severe abdominal pain, motor neuropathy, hyponatremia, and dark urine after starting oral contraceptives. Urine shows elevated porphobilinogen (PBG) and delta-aminolevulinic acid (ALA). The diagnosis is acute intermittent porphyria (AIP). What enzyme is deficient, and why do hormonal medications precipitate attacks?

• A ALA dehydratase; oral contraceptives directly inhibit this enzyme
• B Uroporphyrinogen III synthase; estrogens prevent feedback inhibition of ALAS2
• C Coproporphyrinogen oxidase; progesterone upregulates this enzyme, causing precursor overflow
• D Hydroxymethylbilane synthase (porphobilinogen deaminase); estrogens induce hepatic ALA synthase 1 (ALAS1), increasing porphyrin precursor flux past the enzymatic bottleneck ✓

Explanation

AIP results from ~50% deficiency of hydroxymethylbilane synthase (HMBS/PBGD), the third enzyme of heme synthesis. During attacks, ALAS1 (the rate-limiting, regulated enzyme) is induced by fasting, hormonal changes, or drugs that increase demand for hepatic cytochrome P450s. Estrogens in oral contraceptives induce CYP enzymes, upregulating ALAS1 via transcription factor NRF1/NRF2 and PGC-1α. The increased flux of ALA and PBG overwhelms the deficient HMBS, causing accumulation of these neurotoxic precursors. Treatment includes heme arginate (IV) to suppress ALAS1 by end-product feedback, and high-carbohydrate intake to activate insulin signalling that represses ALAS1.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.